Serotonergic agents

ABSTRACT

Novel piperazine derivatives are provided having the formula  
                 
 
wherein R 1  is cyano, nitro, trifluoromethyl or halogen, or pharmaceutically acceptable acid addition salts thereof, which are useful as 5-HT 1A  receptor antagonists.

This is a continuation of co-pending application Ser. No. 10/218,251,filed on Aug. 14, 2002, which is a continuation of application Ser. No.10/010,575, filed Nov. 13, 2001, which claims the benefit of provisionalapplication Ser. No. 60/253,301, filed Nov. 28, 2000 and provisionalapplication Ser. No. 60/297,814, filed Jun. 13, 2001, each of which ishereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

This invention relates to novel piperazine derivatives, to their use andto pharmaceutical compositions containing them. The novel compounds areuseful as 5-HT_(1A) binding agents, particularly as 5-HT_(1A) receptorantagonists.

BACKGROUND

U.S. Pat. No. 6,127,357 discloses compounds of the general formula (I):

and pharmaceutically acceptable acid addition salts thereof wherein:

-   A is alkylene chain of 2 to 4 carbon atoms optionally substituted by    one or more lower alkyl groups,-   Z is oxygen or sulfur,-   R is H or lower alkyl,-   R¹ is a mono or bicyclic aryl or heteroaryl radical,-   R² is a mono or bicyclic heteroaryl radical, and-   R³ is hydrogen, lower alkyl, cycloalkyl, cycloalkenyl,    cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl,    heteroaryl(lower)alkyl, a group of formula —NR⁴R⁵ [where R⁴ is    hydrogen, lower alkyl, aryl or aryl(lower)alkyl and R⁵ is hydrogen,    lower alkyl, —CO(lower)alkyl, aryl, —Coaryl, aryl(lower)alkyl,    cycloalkyl, or cycloalkyl-(lower)alkyl or R⁴ and R⁵ together with    the nitrogen atom to which they are both attached represent a    saturated hytrocyclic ring which may contain a further heteroatom],    or a group of formula OR⁶ [where R⁶ is lower alkyl, cycloalkyl,    cycloalkyl(lower)alkyl, aryl, aryl(lower)alkyl, heteroaryl or    heteroaryl(lower)alkyl].

WO 97/03982 discloses compounds of the general formula (II):

including enantiomers and the pharmaceutically acceptable acid additionsalts thereof.

The compounds of formula (II) fall within the disclosure of U.S. Pat.No. 6,127,357 but are not specifically disclosed therein. Compounds ofFormula II were taught to have potent 5-HT_(1A) antagonist activity invivo when administered by the oral route.

DETAILED DESCRIPTION OF THE INVENTION

Novel compounds of the invention have the structural formula (III):

wherein R₁ is cyano, nitro, trifluoromethyl or halogen, orpharmaceutically acceptable acid addition salts thereof.

Halogen, as used herein, refers to chlorine, fluorine, bromine andiodine.

The compounds of Formula III contain an asymmetric carbon atom.Accordingly, they may exist in different stereoisomeric forms. In somepreferred embodiments the R stereoisomer (Formula IIIa) is preferred.

In accordance with some embodiments of the invention, the (R)stereoisomer is substantially free of the (S) stereoisomer.Substantially free, as used herein means that the compound is made up ofa significantly greater proportion of its (R) stereoisomer than the (S)stereoisomer. In preferred embodiments the compound is made up of atleast about 90% by weight of its (R) stereoisomer and about 10% byweight or less of its (S) stereoisomer. In other embodiments of theinvention, the compound is made up of at least about 99% by weight ofits (S) stereoisomer and about 1% by weight or less of the (R)stereoisomer. Preferred stereoisomers may be isolated from racemicmixtures by any method known to those skilled in the art, including highperformance liquid chromatography (HPLC) and the formation andcrystallization of chiral salts. See, for example, Jacques, et al.,Enantiomers, Racemates and Resolutions (Wiley Interscience, New York,1981); Wilen, S. H., et al., Tetrahedron 33:2725 (1977); Eliel, E. L.Stereochemistry of Carbon Compounds (McGraw-Hill, NY, 1962); Wilen, S.H. Tables of Resolving Agents and Optical Resolutions p. 268 (E. L.Eliel, Ed., Univ. of Notre Dame Press, Notre Dame, Ind. 1972).

The most preferred compounds of the invention are(R)-4-Cyano-N-{2-[4-(2,3-dihydro-benzo[1,4]dioxin-5-yl)-piperazin-1-yl]propyl}-N-pyridin-2-yl-benzamide;and pharmaceutically acceptable acid addition salts thereof.

The pharmaceutically acceptable salts are the acid addition salts whichcan be formed from a compound of the above general formula and apharmaceutically acceptable acid such as, for example, benzoic,phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic, malic,mandelic, mucic, nitric, fumaric, succinic, tartaric, acetic, lactic,pamoic, pantothenic, benzenesulfonic, or methanesulfonic acid. In someembodiments of the invention the preferred acid addition salt ishydrochloric acid.

The compounds of the present invention can be prepared by known methodsfrom known starting materials which are available by conventionalmethods. For example the compounds may be prepared by the generalmethods disclosed in EP-A-0512755 and WO 97/03982.

Such disclosed methods include acylating an amine of formula (IV) with aknown benzoyl chloride (V) or an alternative acylating derivativethereof. Examples of acylating derivatives include the acid anhydride,imidazolides (e.g. obtained form carbonyldiimidazole), or activatedesters.

wherein R₁ is cyano, halogen, trifluoromethyl or nitro.

Novel compounds of the present invention are potent 5-HT_(1A) bindingagents which selectively binds to the 5-HT_(1A) receptor. Furthermore,the novel compounds of the invention are 5-HT_(1A) receptor antagonistswhen tested by standard pharmacological procedures.

In addition, the novel compounds of formula (III) are unique frompreviously disclosed 5HT_(1A) receptor antagonists in that they possessa superior duration of action as a 5-HT_(1A) receptor antagonist whenadministered in vivo.

EXAMPLES

The present invention is illustrated by reference to the followingexample. Those skilled in the art of organic synthesis may be aware ofstill other synthetic routes to the invention compound. The reagents andintermediates used herein are either commercially available or preparedaccording to standard literature procedures.

Example 1(R)-4-Cyano-N-{2-[4-(2,3-Dihydro-Benzo[1,4]dioxin-5-yl)-Piperazin-1-yl]-Propyl}-N-Pyridin-2-yl-Benzamide

A solution of{(R)-2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazin-1-yl]propyl}-pyridin-2-ylamine(0.846 g, 2.38 mmol) in dichloromethane (20 mL) was treated at 0° C.with the dropwise addition of a dichloromethane solution of4-cyanobenzoyl chloride (1.1 equivalents, 2.63 mmol in 5 mL). Afterstirring for 16 hours the mixture was poured onto hexane (100 mL) toprecipitate the titled compound as its mono-hydrochloride salt (whitesolid, 1.2 g, 97% yield), which was recrystallized fromdichloromethane/hexane.

MS (+) 484 (M+H)⁺.

m.p. 239-240° C.

[α] 25/D=+56 (c=0.6, MeOH)

Elemental Analysis for: C₂₈H₂₉N₅O₃•1.0 HCl

Calculated: C, 64.67; H, 5.81; N, 13.47:

Found: C, 64.69; H, 5.93; N, 13.52:

In order to demonstrate the superior duration of action of the compoundsof formula (III), Example 1 was compared to representative compounds ofU.S. Pat. No. 6,127,357 and WO 97/03892.

Representative compounds of U.S. Pat. No. 6,127,357 possess acyclohexylamide moiety and a 2-methoxyphenylpiperazine grouping. Themost potent example of this general structure (and the most potentcompound taught in U.S. Pat. No. 6,127,357) is compound A, described as“example 3” in U.S. Pat. No. 6,127,357. The only other class ofcompounds in U.S. Pat. No. 6,127,357 for which data are given is thatwhich possess a cyclohexylamide moiety and a benzodioxinylpiperazinegrouping (“Example 17” in U.S. Pat. No. 6,127,357). A small subset ofthis class of compounds is specifically claimed in WO97/03892, with thepreferred compound being compound B (“example A1” in WO97/03892).Therefore, these two preferred examples from EP-A-0512755 and WO97/03892 have been chosen as representatives for comparison to thecompounds of formula (III).

EXAMPLE 2 Binding Profile

Compounds were tested for binding to cloned human 5-HT_(1A) receptorsstably transfected into CHO cells using [³H]8-OH-DPAT as the 5-HT_(1A)radioligand (according to general procedure described in J. Dunlop etal., J. Pharmacol. Tox. Methods, 40, 47-55 (1998)). As shown in Table 1,compounds of the present invention display high affinity for the 5HT1receptor.

EXAMPLE 3 In Vitro Functional Activity

A clonal cell line stably transfected with the human 5-HT_(1A) receptorwas utilized to determine the intrinsic activity of compounds (accordingto the general procedure described in J. Dunlop et al., J. Pharamcol.Tox. Methods, 40, 47-55 (1998)). Data are provided in Table 1. As shownin Table 1, compounds of the present invention antagonized the abilityof 10 nM 8-OH-DPAT to inhibit forskolin-stimulated cAMP production in aconcentration-related fashion. TABLE 1 5-HT_(1A) Antagonist Activity5-HT_(1A) Affinity cAMP Assay Compound Ki (nM) IC₅₀ (nM) Example 1 1.625 Compound A 0.96 7 Compound B 0.97 20

EXAMPLE 4 In Vivo Functional Activity

The ability of the compounds to function in vivo as 5-HT_(1A)antagonists was assessed in rats using a Fixed Responding Model (D.Blackman, in “Operant Conditioning: An Experimental Analysis ofBehavior”, J. Butcher, ed., Methuen and Co., Ltd., London). In thismodel rats are trained to respond (lever pressing) under a fixed-ratio30 schedule of food presentation in order to receive a food pelletreinforcer. Administration of the 5-HT_(1A) agonist 8-OH-DPAT reducesthe control response rate (assessed by administration of vehicleplacebo). The 5-HT_(1A) antagonist activity of a test compound isdetermined by measuring its ability to antagonize this agonist-induceddecrease in response rate. A full antagonist effect is considered one inwhich the test compound completely reverses the agonist-induced responserate, returning it to control levels. The data given in Table 2demonstrate that a 1 mg/kg dose of the compound of Example 1 completelyreverses the decrease in response rate induced by administration of a0.3 mg/kg dose of 8-OH-DPAT. Thus, compounds of the present inventionfunction as 5-HT_(1A) antagonists in vivo. TABLE 2 Response Rate(responses/second) Vehicle 8-OH-DPAT 8-OH-DPAT (0.3 mg/kg sc) +(Control) (0.3 mg/kg sc) Example 1 (1 mg/kg sc) 2.4 ± 0.5 0.5 ± 0.2 2.5± 0.2

EXAMPLE 5 Duration of Action in Vivo

The duration of action in the Fixed Responding Model was assessed bypre-treating animals with test compound and then challenging with a 0.3mg/kg dose of the 5-HT_(1A) agonist 8-OH-DPAT at various time intervalsafter the administration of test compound. All drug and vehicleadministrations were made by the subcutaneous route. Doses of the testcompounds selected for comparison were those which caused a ten-foldshift in the 8-OH-DPAT dose-response curve when administered 30 minutesprior to agonist. The doses selected for the duration of actioncomparison are listed in Table 3. TABLE 3 Dose Which Shifts AgonistDose-response Curve by Test Compound 10-fold (mg/kg, sc) Compound A(FIG. 1) 0.03 Compound B (FIG. 1) 0.1 Example 1 1.0

Data are presented for pre-treatment of the animals with test compoundat 0.5 hours, 2 hours, and 4 hours prior to administration of a 0.3mg/kg dose of 8-OH-DPAT. Results are normalized to control values, with100% being the control response rate observed when vehicle isadministered rather than the agonist 8-OH-DPAT. TABLE 4 % Response Rate0.5 hour 2 hour 4 hour Compound pretreatment pretreatment pretreatmentCompound A + 90 ± 3 55 ±28 41 ± 26 8-OH-DPAT Control + 23 ± 9 3 ± 1 3 ±1 8-OH-DPAT Compound B + 100 ± 11 71 ± 12 27 ± 14 8-OH-DPAT Control + 21± 9 42 ± 6  42 ± 6  8-OH-DPAT Example 1 + 100 ± 7  118 ± 13  99 ± 168-OH-DPAT Control + 29 ± 6 35 ± 10 35 ± 10 8-OH-DPAT

As can be seen from Table 4, all three test compounds (Compound A, Band. Example 1) completely antagonize the agonist-induced decrease inresponding 30 minutes after their administration, returning the responserate to control levels. However, when agonist is given 2 hours followingtest drug administration (Column 3), the 5-HT_(1A) antagonist effects ofcompounds A and B no longer return the response rate to control levelswhile Example 1 still displays complete 5-HT_(1A) antagonist effects. Byfour hours post-administration (Column 4), the 5-HT_(1A) antagonisteffects of Compounds A and B are completely lost, while Example 1continues to provide complete antagonism of the agonist-induced decreasein response rate. Thus, the duration of action of Example 1 is longerthan 4 hours, while those of Compounds A and B are somewhere between 30minutes and 2 hours.

The increased duration of action of the novel compounds of the presentinvention, compared to that of the classes of compounds disclosed inU.S. Pat. No. 6,127,357 and WO 97/03892 is particularly advantageous inthat a smaller number of doses of the compound can be administered toproduce a similar therapeutic effect.

Compounds of the present invention may be used to treat a subjectsuffering from CNS disorders such as schizophrenia, (and other psychoticdisorders such as paranoia and mano-depressive illness), Parkinson'sdisease and other motor disorders, anxiety (e.g. generalized anxietydisorders, panic attacks, and obsessive compulsive disorders),depression (such as by the potentiation of serotonin reuptake inhibitorsand serotonin norepinephrine reuptake inhibitors), Tourette's syndrome,migraine, autism, attention deficit disorders and hyperactivitydisorders. Compounds of the present invention may also be useful for thetreatment of sleep disorders, social phobias, pain, thermoregulatorydisorders, endocrine disorders, urinary incontinence, vasospasm, stroke,eating disorders such as for example obesity, anorexia and bulimia,sexual dysfunction, and the treatment of alcohol, drug and nicotinewithdrawal.

Compounds of the present invention are also useful for the treatment ofcognitive dysfunction. Thus, compounds of the present invention may beuseful for the treatment of cognitive dysfunction associated with mildcognitive impairment (MCI)) Alzheimer's disease and other dementiasincluding Lewy Body, vascular, and post stroke dementias. Cognitivedysfunction associated with surgical procedures, traumatic brain injuryor stroke may also be treated in accordance with the present invention.Further, compounds of the present invention may be useful for thetreatment of diseases in which cognitive dysfunction is a co-morbiditysuch as, for example, Parkinson's disease, autism and attention deficitdisorders.

“Provided”, as used herein with respect to providing a compound orsubstance covered by this invention, means either directly administeringsuch a compound or substance, or administering a prodrug, derivative, oranalog which will form an equivalent amount of the compound or substancewithin the body. Prodrugs can be prepared such as described in Design ofProdrugs, Bundgaard, H. ed., (Elsevier, New York 1985); Prodrugs asNovel Drug Delivery Systems, Higuchi, T and Stella, V. eds, (AmericanChemical Society, Washington, D.C. 1975); Design of BiopharmaceuticalProperties through Prodrugs and Analogs, Roche, E. ed., (AmericanPharmaceutical Association. Academy of Pharmaceutical Sciences,Washington, D.C., 1977); and Metabolic Considerations in Prodrug Design,Balant, L. P. and Doelker, E. in Burger's Medicinal Chemistry amd DrugDiscovery, Fifth Edition, Wolff, M., ed, Volume 1, pages 949-982, (JohnWiley & Sons, Inc. 1995).

The compounds of the present invention may be administered orally orparentally, neat or in combination with conventional pharmaceuticalcarriers. Applicable solid carriers can include one or more substanceswhich may also act as flavoring agents, lubricants, solubilizers,suspending agents, fillers, glidants, compression aids, binders,tablet-disintegrating agents or encapsulating materials. In powders, thecarrier is a finely divided solid which is in admixture with the finelydivided active ingredient. In tablets, the active ingredient is mixedwith a carrier having the necessary compression properties in suitableproportions and compacted in the shape and size desired. The powders andtablets may contain up to 99% of the active ingredient. Suitable solidcarriers include, for example, calcium phosphate, magnesium stearate,talc, sugars, lactose, dextrin, starch, gelatin, cellulose, methylcellulose, sodium carboxymethyl cellulose, polyvinylpyrrolidine, lowmelting waxes and ion exchange resins. Liquid carriers may be used inpreparing solutions, suspensions, emulsions, syrups and elixirs. Theactive ingredient of this invention can be dissolved or suspended in apharmaceutically acceptable liquid carrier such as water, an organicsolvent, a mixture of both or pharmaceutically acceptable oils or fat.The liquid carrier can contain other suitable pharmaceutical additivessuch as solubilizers, emulsifiers, buffers, preservatives, sweeteners,flavoring agents, suspending agents, thickening agents, colors,viscosity regulators, stabilizers or osmo-regulators. Suitable examplesof liquid carriers for oral and parenteral administration include water(particularly containing additives as above, e.g., cellulosederivatives, preferably sodium carboxymethyl cellulose solution),alcohols (including monohydric alcohols and polyhydric alcohols, e.g.,glycols) and their derivatives, and oils (e.g., fractionated coconut oiland arachis oil). For parenteral administration the carrier can also bean oily ester such as ethyl oleate and isopropyl myristate. Sterileliquid carriers are used in sterile liquid form compositions forparenteral administration. Liquid pharmaceutical compositions which aresterile solutions or suspensions can be utilized by, for example,intramuscular, intraperitoneal or subcutaneous injection. Sterilesolutions can also be administered intravenously. Oral administrationmay be either in liquid or solid composition form. Preferably, thepharmaceutical compositions containing the present compounds are in unitdosage form, e.g., as tablets or capsules. In such form, the compositionis sub-divided in unit dosages containing appropriate quantities of theactive ingredients. The unit dosage forms can be packaged compositions,for example, packaged powders, vials, ampoules, prefilled syringes orsachets containing liquids. Alternatively, the unit dosage form can be,for example, a capsule or tablet itself, or it can be the appropriatenumber of any such compositions in package form. The therapeuticallyeffective dosage to be used may be varied or adjusted by the physicianand generally ranges from 0.5 mg to 750 mg, according to the specificcondition(s) being treated and the size, age and response pattern of thepatient.

The present invention may be embodied in other specific forms withoutdeparting from the spirit and essential attributes thereof andaccordingly, reference should be made to the appended claims, ratherthan to the foregoing specification, as indicating the scope of theinvention.

1-5. (canceled)
 6. A method for treating sexual dysfunction in a patientin need thereof, the method comprising providing to the patient atherapeutically effective amount of a compound of formula (III):

wherein R₁ is cyano, nitro, trifluoromethyl or halogen, orpharmaceutically acceptable acid addition salts thereof. 7-12.(canceled)
 13. The method of claim 6, wherein the compound is(R)-4-cyano-N-{2-[4-(2,3-dihydrobenzo[1,4]dioxin-5-yl)piperazine-1-yl]-propyl}-N-pyridin-2-yl-benzamide.